Introduction

Multiple myeloma (MM) is a heterogeneous, incurable malignancy, characterised by remissions and subsequent relapses.1,2 MM predominantly affects the elderly, with a median age at diagnosis around 70 years, and as such can present a number of challenges.3–6 Elderly patients may be frail and suffer from multiple comorbidities that affect symptom burden and quality of life.3,5 In addition, age-related deterioration in organ function can affect the pharmacokinetics and pharmacodynamics of drugs, and therefore the maximum efficacy and tolerability of MM treatment regimens.5 Consequently, age may impact treatment decisions, resulting in suboptimal treatment for elderly patients.4,5 Treatment toxicities can also adversely affect patient quality of life and present logistical challenges that place a further burden on patients.7

High-risk cytogenetic features are another factor associated with a poor prognosis.8–11 The presence of the chromosomal deletion (del[17p]) or one of the translocations t(4;14), t(14;16) and t(14;20) has been associated with significantly poorer overall survival (OS) compared with standard-risk cytogenetic features.12–14 Other cytogenetic risk features, such as gains in chromosome 1q, are also associated with inferior OS outcomes.14 Furthermore, it has been reported that prognosis is worse in patients with more than one adverse cytogenetic risk feature than in patients with a single cytogenetic risk feature.15

It is recognised that maintaining long-term disease control is a key factor for survival in MM, with durability of disease control associated with a better prognosis.16–18 Combining treatments with different mechanisms of action (eg proteasome inhibitors [PIs] with immunomodulatory drugs [IMiDs] or histone deacetylase [HDAC] inhibitors) is associated with a more durable and deeper response than that seen with monotherapy. Data suggest that the multiple and overlapping effects of the different classes of MM agents may lead to the disruption of tumour cell growth and survival.19,20 In particular, promising results have been obtained from phase 3 trials with PIs combined with IMiDs and corticosteroids. Such triplet combinations have been shown to improve response and prolong progression-free survival (PFS) in MM patients compared with doublet therapy,19,21,22 with some combinations also conferring benefits in OS.23–28 Furthermore, triplet combination therapy with PIs, IMiDs and corticosteroids have shown efficacy across a range of patient subgroups, including those with high-risk cytogenetic features.27,28

Continuous therapy is a treatment approach that is supported by the observation that even patients with complete response (CR) can have residual disease. It is aimed at achieving a deeper remission through constant suppression of the survival and proliferation of tumour cells.29 Several studies have shown promising efficacy with the use of continuous therapy in the treatment of MM; when compared with fixed-duration therapies, continuous therapies were associated with improved long-term disease control and patient outcomes.30–33 However, challenges with the use of long-term continuous therapy need to be taken into consideration, such as cumulative toxicities, tolerability, impact on lifestyle and early termination of treatment, making it important to consider patient- and treatment-related factors when prescribing therapy in a patient with MM.30,34–36

Of particular importance is the need for easy-to-administer regimens with good tolerability that support long-term treatment duration, and thereby long-term disease control and maintained quality of life, while also providing benefits in survival outcomes.35

Treatment complexity, regimen intensity, chemotherapy unit capacity and costs all pose challenges to the delivery of long-term treatment in MM.35,37 All-oral triplet regimens that patients can take at home would be a valuable addition to the treatment armamentarium for continuous therapy in MM. Such regimens have the overarching goal of attaining a long-term treatment approach that achieves sustained tumour control, with good tolerability and minimal additional burden on the patient and healthcare systems.

Ideal therapies for MM patients are those that are highly efficacious in a variety of genetic risk groups, are well tolerated and so combine easily with standard of care regimens, and have a convenient mode of administration to facilitate long-term compliance.

Professor Kwee Yong and Dr Rakesh Popat

Introducing ixazomib

The unmet needs in MM led to the development of NINLARO®▼ (ixazomib capsules), the first oral PI for relapsed and/or refractory MM (RRMM), which is licensed in combination with lenalidomide and dexamethasone (Rd), thus providing an all-oral triplet therapy regimen to patients.38 Ixazomib is a highly selective and reversible PI that targets key processes inside myeloma cells and the bone marrow microenvironment.38 The drug preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S core of the 26S proteasome, inducing apoptosis of MM cell lines in vitro.39 Ixazomib also produces effects within the bone marrow microenvironment, including inhibition of stromal cell-induced proliferation of myeloma cells, inhibition of angiogenesis, promotion of osteoblast activity, and inhibition of osteoclast activity.40–41 Aside from its oral route of administration, ixazomib differs from other PIs such as bortezomib and carfilzomib in both structure and function.39 Firstly, carfilzomib exhibits irreversible binding to proteasomes, in contrast with ixazomib and bortezomib, which are reversible PIs.39 Furthermore, pre-clinical studies have demonstrated that ixazomib dissociates approximately six-fold faster from proteasomes than bortezomib.39 This may lead to superior tissue penetration and biological activity of ixazomib, and may act to reduce bone osteolysis, a common and debilitating feature of MM.39

The major clearance mechanism for ixazomib is metabolism by multiple cytochrome P450 (CYP) enzymes and non-CYP proteins, and it is excreted primarily in the urine (62%) and faeces (22%).38 An open-label, phase 1/2 trial of ixazomib plus Rd in MM patients established a terminal half-life of 3.5–10.5 days, supporting weekly dosing with ixazomib.42 Early-phase clinical trial data demonstrated that ixazomib given once weekly in combination with Rd achieved 58% CR or a very good partial response (VGPR).42 Adverse events (AEs) (including peripheral neuropathy) were generally manageable.42 Supported by further data from a pivotal, phase 3 trial, ixazomib became the first and currently the only oral PI licensed in combination with Rd in MM patients who have received at least one prior therapy.38 The recommended dosing regimen of ixazomib is one 4mg* capsule taken on days 1, 8 and 15 of 28-day cycles, in combination with Rd at the standard dosing schedules (see Figure 4).38

The ixazomib plus Rd combination was shown to achieve rapid and sustained responses across a broad group of patients irrespective of cytogenetic risk, compared with Rd alone. Adding ixazomib to Rd is generally well tolerated with a manageable AE profile and offers the convenience of an all-oral regimen with minimal additional burden on patients and the health system.28,38

Efficacy

Although long-term treatment can improve outcomes in MM, this may be difficult to achieve due to a number of challenges such as chemotherapy unit capacity and costs, treatment complexity, and early termination of therapy due to increased toxicities.11,30,34–36 The availability of an active and well-tolerated agent with a convenient mode of administration to aid continuous therapy and treatment compliance provides an opportunity to achieve sustained disease control in MM.28,38

The efficacy and safety of oral ixazomib added to Rd for the treatment of patients with RRMM has been studied in the first global, double-blind, placebo-controlled, phase 3 trial investigating an oral PI (TOURMALINE-MM1).28 Patients with RRMM who had received 1–3 prior therapies (including PIs and IMiDs), had measurable disease, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 were eligible for inclusion.28 A broad range of RRMM patients were enrolled, including patients with high-risk cytogenetic features, mild-to-moderate renal impairment, and primary refractory disease (Table 1).28,38 Overall, 722 patients were randomised in the trial; patients received either oral ixazomib 4mg or matching placebo given on days 1, 8 and 15 of 28-day cycles, and all patients received oral lenalidomide 25mg on days 1–21 (adjusted for renal function) and oral dexamethasone 40mg on days 1, 8, 15 and 22 (Figure 1).28

Table 1. Patients enrolled in TOURMALINE-MM 28,38

Figure 1. Study design and treatment randomisation

The primary endpoint was PFS, assessed by independent review.28 Secondary endpoints included OS (overall and in patients with del[17p]), overall response rate, and PFS in patients with high-risk cytogenetic abnormalities (defined as del[17p], t[4;14] or t[14;16]).28 At the first and final analysis for PFS (October 30, 2014), median follow-up was 14.8 months in the ixazomib plus Rd group and 14.6 months in the placebo plus Rd group.28 A second pre-specified analysis was conducted to assess OS at a median follow-up of approximately 23 months.28

Progression-free survival

Adding oral ixazomib to Rd significantly extended PFS by 5.9 months compared with placebo plus Rd at 14.7 months’ median follow-up.28 Median PFS was 20.6 months versus 14.7 months, respectively, and the hazard ratio (HR) for disease progression or death in the ixazomib plus Rd group was 0.74 (95% confidence interval [CI], 0.59–0.94; p=0.01), representing a clinically meaningful 35% improvement in PFS versus placebo plus Rd (Figure 2).28 These results are consistent with previous studies that have shown triplet regimens to be more efficacious than doublet regimens,23–27,43 including three studies of Rd plus a third agent versus Rd alone in patients with RRMM.24,27,44

Overall survival

In a planned interim analysis of OS at 23 months’ median follow-up, median OS was not reached in either group.28 There were 81 deaths with the ixazomib plus Rd regimen and 90 deaths with the placebo plus Rd regimen, representing 35% of the required number of deaths for final OS analysis. Follow-up is ongoing.28

Subgroup analysis

Compared with placebo plus Rd, the addition of oral ixazomib to Rd extended PFS across a range of pre-specified patient subgroups including: those with high-risk cytogenetic abnormalities, patients who had received two or three prior therapies, patients with prior PI exposure and patients with mild-to-moderate renal impairment (Figure 3).28 There were no significant interactions between subgroups and study group assignment.28

Adding oral ixazomib to Rd extended PFS when compared with placebo plus Rd irrespective of patients’ cytogenetic risk profile.28 Overall, 75 patients (21%) in the ixazomib plus Rd group and 62 patients (17%) in the placebo plus Rd group had high-risk cytogenetic abnormalities.28 Median PFS in these patients was 21.4 months and 9.7 months, respectively (HR for disease progression or death in the ixazomib group of 0.54 [95% CI, 0.32–0.92; p=0.02]).28 Median PFS with ixazomib plus Rd versus placebo plus Rd was 21.4 months versus 9.7 months, respectively (HR 0.60 [95% CI, 0.29–1.24]) among those patients with chromosomal deletion del(17p), and 18.5 months versus 12.0 months, respectively (HR 0.65 [95% CI, 0.25–1.66]) among those patients with translocation t(4;14) without del(17p) or t(14;16).28 In contrast with the placebo plus Rd group and results from other phase 3 trials of Rd alone, in which presence of high-risk cytogenetic features were associated with a poorer PFS than a standard-risk cytogenetic profile, use of oral ixazomib plus Rd in patients with high-risk cytogenetics (including those with del[17p]) resulted in a similar median PFS to that seen in standard-risk patients.15,28,45

While the overall response rate for ixazomib plus Rd is marginally higher than Rd, the depth of response (VGPR or CR) is much improved with the addition of ixazomib. Maintaining this will lead to better outcomes.

Professor Kwee Yong and Dr Rakesh Popat

Tolerability

Achieving an acceptable tolerability profile is crucial in optimising the survival benefit derived from MM therapies. Hence, it is notable that the safety profile with ixazomib after a longer exposure (at second analysis, 23 months) was consistent with that at the first analysis (14.7 months).28 Current therapies have agent-specific toxicity profiles that may impact schedule delivery, such as peripheral neuropathy. Strategies implemented to manage such AEs, eg dose reduction and interruptions, may, especially in the early stages of treatment, shorten the length of therapy and reduce survival in patients with MM.46 Optimisation of clinical outcomes relies on the maintenance of long-term therapy and it is therefore imperative that the tolerability profile of an agent is acceptable in order to facilitate the best outcomes.46

Adverse events, treatment discontinuation and dose reduction

At 23 months’ median follow-up, patients in the ixazomib plus Rd group and the placebo plus Rd group had received a median of 17 cycles (range 1–34) and 15 cycles (range 1–34) of treatment, respectively.28 Oral ixazomib plus Rd was generally well-tolerated and the AEs were manageable with supportive care. The most frequently reported AEs were gastrointestinal events, rash, thrombocytopenia, peripheral oedema, peripheral neuropathy and back pain (Table 2).28 AEs were generally grade 1 and 2 and manageable with supportive care. Importantly, there were no cardiovascular or renal safety signals observed in the study with ixazomib plus Rd.28 Thrombocytopenia was increased in the ixazomib plus Rd arm (all, 31%; grade 3/4, 12%/7%) versus the placebo plus Rd arm (all, 16%; grade 3/4, 5%/4%), but did not result in an increase in bleeding events or platelet transfusions.28 The incidence of grade 3 peripheral neuropathy was 2% across both groups and there were no cases of grade 4 peripheral neuropathy.28

Table 2. Adverse events of clinical importance in the safety population at the 23-month analysis28,38

Most patients (76%) were able to continue on oral ixazomib plus Rd treatment at their starting dose without dose modifications.47 The median relative dose intensity for Rd was similar in the two treatment groups; the median relative dose intensity for ixazomib (97.4%) was similar to that for placebo (98.8%) at 23 months’ median follow-up.28 Overall, 17% of patients discontinued the ixazomib plus Rd regimen and 14% discontinued the placebo plus Rd regimen because of AEs.28

Management of adverse events with supportive care

It is important that new therapies are well tolerated and treatment-emergent toxicities are readily managed. Gastrointestinal toxicities may occur with the use of ixazomib and with Rd, and may require the use of antiemetics, antidiarrhoeals and supportive care.28,38 In TOURMALINE-MM1, diarrhoea was managed with the use of antidiarrhoeal agents (such as loperamide) and dose adjustment of lenalidomide or ixazomib.28 Ixazomib should be withheld in cases of grade 3/4 gastrointestinal toxicities, with the dose being resumed at the next lowest dose following recovery (to baseline condition or at most grade 1). Monitoring of serum potassium level is recommended in cases of severe diarrhoea.38

Rash was managed with the use of antihistamines or topical steroids, and dose adjustments, during the ixazomib trial.28 An alternating dose modification approach is recommended for ixazomib and lenalidomide for the overlapping toxicity of rash.38 Patients receiving ixazomib should also be monitored for potential thrombocytopenia (at least monthly) and for onset of peripheral sensory neuropathy.38 Ixazomib should be temporarily withheld in cases of grade 1 peripheral neuropathy with pain, or grade 2 or 3 peripheral neuropathy, and should be discontinued in patients with grade 4 peripheral neuropathy.38

We have found ixazomib to be a very well-tolerated agent that is easy to deliver, in conjunction with Rd. The complementary mechanism of action and minimal non-overlapping toxicity profile means that full dose intensity can be maintained, allowing patients to gain durable benefit from the combination. It is unusual to stop ixazomib due to toxicity; dose reductions are usually sufficient to maintain dosing.

Professor Kwee Yong and Dr Rakesh Popat

Quality of life

Quality of life for MM patients can be impacted by disease symptoms and treatment toxicity.3 Balancing these factors and also taking patient convenience into account can help increase adherence, which in turn may optimise treatment outcomes. In TOURMALINE-MM1, the efficacy and tolerability profile of the all-oral ixazomib plus Rd regimen allowed patients’ global quality of life to be maintained, an important aspect with continuous therapy.28 Meaningful PFS extension was achieved without negatively impacting global quality of life.28 The TOURMALINE-MM1 double-blind study design further adds to the clinical significance of the quality-of-life assessment.28

We have found that our patients maintain anexcellent quality of life while on this regimen.Importantly, the all-oral dosing regimen allowsthem to get on with their lives in between clinicappointments and try and achieve some senseof stability and normality. They can travelwithout missing or delaying doses, which isimportant to many.

Professor Kwee Yong and Dr Rakesh Popat

Simplicity

The benefits gained from efficacious therapies may be limited by reduced adherence due to patients having to travel to clinics for treatment administration and to collect medication. Ixazomib plus Rd offers the convenience of an all-oral regimen, which reduces time in hospital and does not add burden to chemotherapy units. The usual recommended starting dose of oral ixazomib is a single 4mg capsule taken once weekly with Rd at standard dosing (Figure 4).38 For patients with moderate or severe hepatic impairment, severe renal impairment or end-stage renal disease requiring dialysis, the recommended starting dose of oral ixazomib is 3mg.38 Antiviral prophylaxis should be considered to reduce the risk of herpes zoster reactivation.38

Figure 4. 28-day dosing schedule of ixazomib plus Rd38

A similar tolerability profile to that of placebo plus Rd was seen in patients receiving ixazomib plus Rd in the phase 3 trial; despite the limited additional toxicity of ixazomib, patients continued on therapy, resulting in high adherence rates.28 In addition, the ixazomib plus Rd combination required no additional planned hospital visits.38

We have found compliance levels to be very good on this regimen. As our pharmacy pre-dispenses oral chemotherapy, the time patients spend at hospital visits is relatively short. Patients seem to like a once-weekly PI schedule. The most common AEs that we have experienced in our practice were nausea and fatigue, which are generally successfully dealt with by dose adjustments of lenalidomide and dexamethasone, as well as of ixazomib. In particular, we have found thatfatigue can be markedly lessened by reducingsteroid doses.

Professor Kwee Yong and Dr Rakesh Popat

Conclusions

While there have been significant advances in the survival of MM patients, it remains an incurable disease and high-risk patients continue to have poor outcomes. In some patients, MM is a debilitating disease that impacts upon their quality of life, and vulnerable subgroups such as the elderly and patients with high-risk cytogenetic features tend to have a poor prognosis. The development of ixazomib, an oral PI licensed in combination with Rd for the treatment of patients with MM who have received at least one prior therapy, offers the potential to address some of these challenges by facilitating the use of a continuous, combination therapy.

The efficacy and tolerability data from the pivotal TOURMALINE-MM1 trial support the use of ixazomib plus Rd in patients with RRMM; PFS was significantly longer by a median duration of approximately 6 months versus placebo plus Rd, and AEs were manageable with supportive therapy.28 Furthermore, being an all-oral regimen, adding ixazomib to Rd offers convenience and places minimal additional burden on patients and healthcare systems, thereby supporting its long-term use and sustained effectiveness.

Ixazomib is indicated with Rd in the relapsed/refractory setting. Given that most patients in the UK will have received a bortezomib-containing induction regimen, this would be a good option at first or second relapse (assuming funding is available). Elderly and less mobile patients in particular will find this regimen very welcome, as will increasingly busy chemotherapy day units. Ixazomib provides a novel option in the expanding treatment choices for patients with MM. In combination with Rd, this agent is a good choice for those wanting the convenience of an oral regimen and minimal hospital visits.

Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2012;30:2475–82.

Contents

Contributors

Professor Kwee Yong, Professor of Haematology, University College Hospital, London

Dr Rakesh Popat, Consultant Haematologist, University College Hospital, London

Sponsorship

This publication has been commissioned and paid for by Takeda Oncology. Takeda Oncology had editorial input into the writing of this publication. Editorial support was provided by Succinct Medical Communications Ltd.

Disclaimer

KOMs are independent publications provided by Wiley on behalf of sponsoring companies. The responsibility for the content is with the contributors, Takeda Oncology and the publisher, and not with any journal editors. The opinions expressed in this publication are not necessarily those of the publisher or Takeda Oncology.

Date of preparation: January 2017

UK/IXA/1610/0072c

Of particular importance is the need for easy-to-administer regimens with good tolerability that support long-term treatment duration